Emerging drugs in metastatic breast cancer

Background: Breast cancer is the most common cancer among women and comprises 26% of all cancers diagnosed in women in the United States. Among presenting patients, 3 – 6% already have metastatic disease, and 50 – 70% of the remaining patients develop systemic relapse. Recently many new drugs, particularly molecular targeted therapies, have been developed in the field. Objective: To review the current and emerging data on the treatment of metastatic breast cancer, with emphasis on novel therapies that show promise. Methods: PubMed and ASCO annual meeting abstracts were used for a literature search. Results/conclusions: Despite improved response rates, conventional treatments still result only in transient remission in most cases. New therapeutic alternatives and new strategies to overcome drug resistance are needed to improve these results.     

Emerging drugs for endometrial cancer

Introduction: From the dualistic classification that divides endometrial cancer (EC) into two types with distinct underlying molecular profiling, histopathology and clinical behavior, arises a deeper understanding of the carcinogenesis pathways. EC treatment comprises different and multimodal therapeutic approaches, such as chemotherapy, radiation therapy or combinations of novel drugs; however, few of these regimens have truly improved progression-free or survival rates in advanced and metastatic settings.

Areas covered: We reviewed the main molecular pathways involved in EC carcinogenesis through a wide literature search of novel compounds that alone or in combination with traditional drugs have been investigated or are currently under investigation in randomized clinical trials.

Expert opinion: The molecular therapies mainly discussed in this review are potential therapeutic candidates for more effective and specific treatments. In the genomic era, a deeper knowledge about molecular characteristics of cancer provides the hope for the development of better therapeutic approaches. Targeting both genetic and epigenetic alterations, attacking tumor cells using cell-surface markers overexpressed in tumor tissue, reactivating antitumor immune responses and identifying predictive biomarkers represent the emerging strategies and the major challenges.     

Novel strategies for systemic treatment of endometrial cancer

The median survival of women with advanced or recurrent endometrial cancer is less than one year. Of the women with early stage endometrial cancer and poor prognostic factors like high grade or deep myometrial invasion, 40% will recur. Over the last decade, incredible strides have been taken in evaluating systemic therapy for this disease, however, survival rates remain poor. Progestin therapy offers a 10 - 20% response rate and survival of less than one year. Progestins are most effective in women with well-differentiated tumours and long disease-free interval. There is no role for adjuvant progestin therapy in early stage disease. Single-agent chemotherapy with most activity include ifosfamide, cisplatin/carboplatin, doxorubicin and paclitaxel. Combination chemotherapy provides a response rate of 40 - 60%, however, median survival is still less than a year. New areas of research include the identification and evaluation of new active endocrine therapies (i.e., LY-353381.HCl and letrozole), chemotherapeutics (i.e., paclitaxel), evaluating chemotherapeutic agents in combination (i.e., paclitaxel, doxorubicin and platinum), in addition to radiation or instead of radiation. New avenues under development involve the specific molecules and pathways responsible for the initiation and growth of endometrial carcinoma (i.e., Herceptin?). Exciting developments in the understanding of the molecules involved in tumour development and metastasis will allow the development of specific and selective inhibitors.     

Pharmacotherapy of endometrial cancer

Background: Endometrial cancer is the seventh most common malignancy among women worldwide. Despite most cases being diagnosed at an early stage, the death rate has increased steadily over the past 20 years. The lack of an effective, standardized adjuvant treatment for women at a high risk of recurrence has contributed to these disappointing results. Objectives: The goal of this review was to assess the role of hormonal and cytotoxic therapies in the adjuvant treatment of endometrial cancer. Once defined, an evidence-based management algorithm for this neoplasm was proposed. Methods: A thorough literature search was undertaken using the Cochrane and Pubmed databases. Systematic reviews, meta-analyses, and randomized controlled trials were first collected and critically analyzed. Other study types were secondarily considered when pertinent. Conclusions: The choice of the adjuvant therapy in early-stage endometrial cancer must be a patient-specific decision. Preliminary data suggest a role for chemotherapy in high-risk subgroups. However, further research is necessary to confirm this. To date, hormonal therapy has not been widely used in the management of early-stage disease, other than for conservative treatment in a fertility-sparing setting. Both hormonal and chemotherapy represent valuable therapeutic tools for the management of patients affected by advanced disease.     

Emerging drugs for hepatocellular carcinoma

Hepatocellular carcinoma is often diagnosed at an advanced stage, when potentially curative surgical or local ablative therapies are not feasible. There is no effective chemotherapy for hepatocellular carcinoma. Recent advances in cancer biology suggest that a limited number of signalling pathways may be responsible for uncontrolled cell proliferation, the major cellular alteration responsible for the cancer phenotype. Novel anticancer agents target these critical pathways, including the receptor tyrosine kinase pathways, the Wnt/β-catenin signalling pathway, the ubiquitin/proteasome degradation pathway, the DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, telomerase and the cell cycle. These agents hold promise for improving the outcome of patients with intermediate and advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, to achieve long-term survival of the majority of patients, targeted anticancer therapies will need to be coupled with strategies aimed at reversing the progression of chronic liver disease.     

An update on the current pharmacotherapy for endometrial cancer

Introduction: Endometrial cancer (EC) is the most common gynecologic malignancy in the developed world and is increasing in incidence. While the mainstay of treatment for EC is surgery followed by chemotherapy and/or radiation therapy, the available pharmacotherapies are rapidly and constantly evolving. Understanding these new therapies is an important part of the research and clinical care of women with EC. A review of available literature from MEDLINE (1879–2015) was conducted for the historic treatments and current therapies available for endometrial tumors.

Areas covered: This article reviews the current conventional therapies and discusses novel therapeutic agents, some of which are available to clinicians while others are currently being investigated in the preclinical setting.

Expert opinion: Genomic and immunohistochemical characterization of endometrial cancer may soon be the best approach for the identification of aggressive forms of tumor. Targeted therapies will soon be standard in the management of endometrial cancer.     

Emerging drugs for esophageal cancer

Background: Cancer of the esophagus and gastro-esophageal junction is a disorder with a poor prognosis and increasing incidence. Objective: To provide a critical evaluation of current treatment strategies and new developments including targeted therapy for esophageal cancer. Methods: Published clinical trials as well as abstracts were selected regarding chemoradiation or targeted therapy for esophageal cancer. Results/conclusions: Preoperative chemotherapy may offer a survival advantage compared to surgery alone, but the evidence is inconclusive. For preoperative chemoradiation, only 2 of 10 randomized trials showed advanced survival compared to surgery alone, and, therefore, more Phase III trials and, consequently, meta-analyses are needed. Until now, for palliative chemotherapy, no survival benefit has been shown. This is largely due to a lack of studies and difficulties in performing randomized trials. The application of targeted therapy is widespread and reported for several tumor types. For esophageal cancer, most studies have been performed with EGFR inhibitors, including cetuximab, gefitinib, erlotinib and trastuzumab. Limited experience is available with angiogenesis inhibitors, apoptosis inhibitors and COX-2 inhibitors. As yet, targeted therapies are proven to be safe often in combination with chemoradiation, but modestly effective for esophageal cancer. Phase III trials have not been published yet and, therefore, for targeted therapies also, possibly using new concepts, more studies are needed.     

Emerging drugs in colorectal cancer

A raft of novel agents with different modes of action is finally challenging the position of 5-fluorouracil (5-FU) as the gold standard treatment for colorectal cancer. Oral fluoropyrimidines, topoisomerase I inhibitors and new generation platinum compounds are all currently being investigated. There is also increasing interest in the development and use of biological therapies, which may allow treatments to become tailored to individual patients and cause less toxicity than conventional cytotoxics. It is hoped that with the development of these new drugs, the response rates and survival for patients with colorectal cancer will improve from the poor prognosis that many face at present.     

Emerging drugs for biliary cancer

Biliary cancer comprise carcinoma of the gallbladder as well as the intrahepatic, hilar and extrahepatic bile ducts. Furthermore, many different etiologies and risk factors are contributing to the inhomogeneity of this disease. It is often diagnosed at an advanced stage when potentially curative resection is not feasible. Due to the lack of randomised Phase III studies, there is no standard regimen for chemotherapy in biliary cancer. Recent investigations into the underlying molecular mechanisms involved in biliary carcinogenesis and tumour growth have contributed greatly to our understanding of biliary cancer. Through a better understanding of these mechanisms, improved and more specific diagnostic, therapeutic and preventive strategies may be developed. Although fluoropyrimidines and gemcitabine remain the backbone of routine chemotherapy in advanced disease, new agents such as epidermal growth factor receptor blockers and angiogenesis inhibitors may hold promise for improving the outcome for patients with biliary cancer.     

Emerging drugs for renal cell carcinoma

Importance of the field: The treatment of metastatic renal cell carcinoma (RCC) has evolved significantly over the past 5 years and targeted therapy has become the standard of care. However, complete and lasting responses to these drugs are still uncommon. Currently, novel agents are being tested in clinical trials.

Areas covered in this review: We discuss approved targeted agents in RCC and emphasize on emerging therapies. We searched the US National Library of Medicine (PubMed) using the terms ‘renal cell carcinoma’, ‘targeted therapy’ and ‘novel agents’, from 1990 to the present. We also searched for abstracts from the meetings of the American Society of Clinical Oncology and Genitourinary Cancers Symposium from 2007 to the present.

What the reader will gain: This paper provides understanding of the approved treatments for advanced RCC as well as the novel agents and their targeted biological pathways.

Take home message: Despite dynamic and recent advances in the management of metastatic RCC much about the molecular biology of this tumor has yet to be delineated. Even more so, strategies of sequential treatment, combination of targeted drugs, mechanisms of resistance, optimal dosages and scheduling remain areas of potential development interest.     

Therapeutic options for metastatic breast cancer

Metastatic breast cancer (MBC) remains an incurable disease despite ongoing therapeutic advances. Recently there has been progress extending the range of available cytotoxic chemotherapy drugs and optimizing their scheduling. In addition, a greater understanding of tumor biology has led to the development of a number of targeted therapies. Several of these newer agents, such as trastuzumab, lapatinib and bevacizumab, have demonstrated activity in combination with chemotherapy and have improved the prognosis of patients with MBC. We hope that further progress elucidating the pathophysiology and biology of MBC will continue to lead to corresponding advances in treatment.     

Targeting the extracellular signature of metastatic colorectal cancers

Background: Colorectal cancer is a leading cause of tumor death, a consequence primarily of the spreading of malignant cells to liver and lung. Despite a range of interventions for liver metastases, the present knowledge of few specific molecular targets may contribute to late diagnosis and poorly effective therapy. Objective: To review the most innovative methodology employed to profile the signature(s) of metastatic colorectal cancer (mCRC) and to address diagnostic/therapeutic agents. Methods: A broad range Medline search was conducted, with particular attention to the search terms ‘liver metastasis signature’, in combination with ‘targeting’ and ‘nanotechnology’. Results/conclusions: Studies aimed at the discovery of molecular signatures of cancers and metastasis are ongoing; the future of cancer/metastasis targeting is nanoparticle-mediated drug delivery.     

子宫内膜癌治疗药物的研究进展

药物治疗是子宫内膜癌治疗的重要组成部分,常用药物包括激素治疗药物（孕激素、抗雌激素药物、促性腺激素释放激素激动剂）、化疗药物（紫杉醇、铂类、蒽环类）和靶向药物（表皮生长因子受体拮抗剂、哺乳动物雷帕霉素靶蛋白抑制剂等）。随着研究的深入,越来越多的抗子宫内膜癌新靶点被发现,包括血管内皮生长因子（VEGF）、聚腺苷二磷酸核糖聚合酶（PARP）、程序性死亡受体1（PD-1）和PD-1配体（PD-L1）,中药和天然单体化合物也是目前的研究热点。对子宫内膜癌治疗药物的作用机制及研究进展进行综述,以期对该病治疗及新药研发有所裨益。     

Emerging drugs for urothelial carcinoma

Introduction: Advanced urothelial carcinoma is associated with a poor prognosis. In the metastatic setting, the response rate to first-line, cisplatin-containing chemotherapy is high, but survival is poor. Second-line treatment options are limited. Advanced age at diagnosis and the presence of comorbidities often preclude treatment with cisplatin-containing regimens.

Areas covered: This review addresses the current therapy of urothelial carcinoma, the unmet needs in treatment and the status of drug development in this disease. The molecular targets identified and efforts to incorporate targeted agents into therapy will be addressed.

Expert opinion: There have been no major advances in the treatment of urothelial carcinoma in three decades. Despite high response rates in the first-line setting, survival is limited. Major impediments to improved outcomes include poor durability of response to first-line chemotherapy and lack of second-line treatments. Better understanding in tumor biology has identified multiple targets in urothelial carcinoma; however, such discoveries have yet to lead to the incorporation of targeted agents into the routine treatment of urothelial carcinoma. Multiple ongoing clinical trials are investigating the use of targeted agents in urothelial carcinoma. Continued efforts are underway to better understand the molecular drivers of disease and such efforts are likely to identify additional therapeutic targets.     

A review on the treatment of relapsed/metastatic head and neck cancer

The efficacy of traditional chemotherapy in inducing objective responses and prolonging survival in recurrent or metastatic head and neck cancer has been disappointing. More recent drugs have not proven superior to the classic regimen of cisplatin and 5-fluorouracil. Anti-EGFR monoclonal antibodies, either as single agents or associated to chemotherapy, have been shown to be active and little toxic. Among them, cetuximab has proven to be the most promising. Indeed the Extreme study, which compared the classic couple cisplatin (CDDP) + 5-fluorouracil with the same regimen plus cetuximab, has constituted a remarkable innovation. The results of that trial seem to indicate a third agent added to CDDP and 5-fluorouracil improved both progression-free survival and overall survival in the recurrent or metastatic setting. Unfortunately, the results obtained with the tyrosine kinase inhibitors are less impressive, and additional studies are needed to explore the potentiality of this class of drug. As far as antiangiogenetics are concerned, the research is insufficient for any conclusion to be drawn in terms of efficacy. It is hoped that, in the near future, the most active combination between biological agents and traditional chemotherapy will be found, so that the path successfully taken in other neoplastic diseases may be retraced.     

Emerging drugs for mesothelioma

Malignant mesothelioma is an aggressive, but relatively rare, malignancy, affecting the pleura and peritoneum. The prognosis for malignant pleural mesothelioma (MPM) is poor, with median survival in the range of 8 – 14 months, depending on stage and presentation of disease. Long-term results of available treatments are disappointing not only in terms of prognosis, but also of local control of the disease. Therefore, relief of symptoms and improvement of quality of life parameters are the short-term goals of therapy. In advanced disease not amenable to any local approach, such as surgery, combination chemotherapy represents the current standard of care. At present, the regimen of cisplatin/pemetrexed is the medical treatment of choice. This review summarizes standard chemotherapy options and focusses on the molecular basis of the newest biologically targeted therapies to be implemented in the near future, in the management of MPM.     

Emerging drugs for small-cell lung cancer

Small-cell lung cancer (SCLC) is a rapidly progressing tumor in which chemotherapy has a limited impact on survival. Unfortunately, little progress has been made in the medical management of SCLC during the last 30 years, which is best exemplified by the fact that standard first-line chemotherapy has remained platinum-based over time. On the other hand, improvements in survival have been obtained only with the introduction of innovative radiation strategies such as accelerated hyperfractionation to the thorax for limited-stage disease and prophylactic cranial irradiation for both limited- and extensive-stage disease. However, recent advances in the understanding of SCLC biology have renewed the interest in the clinical development of active drugs for SCLC. In this review, we address the most promising agents under clinical evaluation, discussing both novel chemotherapeutic agents and targeted agents. Particularly, amrubicin, a fully synthetic anthracycline, is a very active agent for SCLC, and ongoing Phase III trials are evaluating this agent either in the first-line setting of extensive-stage or relapsed disease. Among targeted agents, anti-angiogenic strategies and Bcl-2 inhibitors represent the most promising approaches, and they are being specifically tested in combination with and/or as maintenance therapy after first-line platinum-based chemotherapy.     

子宫内膜癌靶向药物治疗研究进展

子宫内膜癌的化疗耐药性问题显著,迫切需要新的治疗方案。随着对肿瘤发病机制和信号传导通路的深入研究,以及表观遗传修饰作用机制的阐明,靶向药物研究为子宫内膜癌的治疗提供了新的方法和手段。本文综述了表皮生长因子受体拮抗剂、血管内皮生长因子抑制剂、PI3K/Akt/mTOR通路抑制剂、PD-1/PD-L1抑制剂和表观遗传修饰抑制剂等靶向药物在子宫内膜癌治疗领域的研究进展,为临床用药提供新思路。     

Emerging drugs for the treatment of pancreatic cancer

Treatment of pancreatic cancer remains challenging today and mostly palliative. Despite many efforts to understand the underlying mechanisms of this aggressive tumoral phenotype and to develop new therapeutic agents, advances in its management and survival benefit are poor. Although gemcitabine remains the backbone of routine therapy in advanced disease, newer drugs, mainly constituted by (multi)targeted agents, represent promising therapeutic areas. In this setting, anti-EGF receptor, antiangiogenic or both therapies combined appear to have valuable potential, providing their optimal and comprehensive development and use in pancreatic cancer. Multitargeted agents, such as receptor tyrosine kinase inhibitor small molecules, combining different therapeutic interventions, also deserve new preclinical and clinical development, supported and paralleled by a translational approach. Over the next few years, we need to identify new target mechanisms in pancreatic carcinogenesis, to rapidly test selected drugs against these targets and imperatively to understand and determine which patients respond and who will benefit from such therapies. Significant advances should be immediately evaluated in the perioperative setting in order to improve the curative approach of this devastating disease.     

Investigational drugs for treating anal cancer and future perspectives

Introduction: Anal cancer is a relatively rare malignancy which comprises about 2.5% of all digestive system malignancies in the United States. The majority of cases are squamous cell carcinoma which is closely related to human papilloma virus (HPV) infection. Despite high cure rates with chemoradiation alone, 10 – 20% of patients do develop metastatic disease with little data to guide their treatment.

Areas covered: In this review article, the authors describe the current standard treatment of early and advanced squamous cell carcinoma of the anal canal based on published data. The authors then describe the new approaches to the disease, focusing on new radio sensitizing agents, systemic targeted drugs and immunotherapy.

Expert opinion: The authors believe that current standard treatment options for squamous cell carcinoma of the anal canal are well defined with acceptable results. However the major challenge in the treatment of anal cancer is the lack of randomized or even large single arm Phase II trials due to rarity of the disease, especially in the metastatic disease. But we are slowly making progress. Currently, the most promising areas of research are immunotherapy, targeted therapy and even HPV prevention. We are eagerly anticipating the results of these studies in order to expand the treatment armamentarium.